Abstract 3799: <i>CDKN2ALow</i>cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance

Abstract Approximately 50% of cancers exhibit decreased CDKN2A expression (CDKN2ALow), which is linked to resistance to immune checkpoint blockade (ICB). The mechanisms driving ICB resistance due to CDKN2A loss alone remain largely unexplored. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement as a consequence of CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2ALow cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation and concurrent zinc depletion in the TME. This reorganization results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through dietary intervention primes macrophage phagocytic activity in response to ICB. Unexpectedly, zinc-reeducated macrophages alone can initiate a robust ICB response in CDKN2ALow tumors whereas T cells are not required. Clinically, macrophages from CDKN2ALow cancer patients have decreased zinc signatures corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2ALow cancer cells directly disrupt macrophage function and ICB efficacy by altering zinc compartmentalization within the tumor. Our data also indicates that zinc dietary intervention may offer a cost-effective and clinically feasible strategy to overcome ICB resistance and improve treatment outcomes in patients with CDKN2ALow tumors. Citation Format: Raquel Buj, Katherine M. Aird. CDKN2A Low cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3799.